NMDA receptor inhibition prevents tolerance to cocaine

Male rats were treated with cocaine by utilizing two different experimental paradigms. One group of animals received a low dose (10 mg/kg, IP) of cocaine for 7 days. A second group received 40 mg/kg IP of cocaine for 3 days. In both experimental groups, half the animals were concomitantly treated with 0.25 mg/kg IP (+)-5methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10- imine maleate (MK-801), a noncompetitive NMDA receptor antagonist. Rats treated with the low dose of cocaine after 7 days developed tolerance to the stimulation of locomotor activity induced by cocaine and by the dopamine D2 agonist quinpirole. Rats treated with 40 mg/kg of cocaine showed a marked behavioral sensitization. Both these effects, tolerance and sensitization, were prevented by coadministration of MK-801, thus suggesting these two phenomena are different aspects of a common neuronal response in which NMDA transmission plays a crucial role.